Evaluation and Treatment of SARINA SCHRAGER, MD, MS; JULIANNE FALLERONI, DO, MPH; and JENNIFER EDGOOSE, MD, MPH University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin

Endometriosis, which affects up to 10 percent of reproductive-aged women, is the presence of endometrial tissue outside of the uterine cavity. It is more common in women with or (70 to 90 percent and 21 to 40 percent, respectively). Some women with endometriosis are asymptomatic, whereas others present with symptoms such as debilitating pelvic pain, , , and decreased . Diagnosis of endometriosis in primary care is predominantly clinical. Initial treatment includes common agents used for primary dysmenorrhea, such as anti-inflammatory drugs, combination /progestin contraceptives, or progestin-only contraceptives. There is some evidence that these agents are helpful and have few adverse effects. Referral to a gynecol- ogist is necessary if symptoms persist or the patient is unable to become pregnant. Laparoscopy is commonly used to confirm the diagnosis before additional treatments are pursued. Further treatments include gonadotropin-releasing analogues, , or surgical removal of ectopic endometrial tissue. These interventions may control symptoms more effectively than initial treatments, but they can have significant adverse effects and limits on dura- tion of therapy. (Am Fam Physician. 2013;87(2):107-113. Copyright © 2013 American Academy of Family Physicians.) ▲ Patient information: ndometriosis is defined as the by the fact that the most commonly affected A handout on this topic is presence of endometrial glandu- sites are closest to the fallopian tubes.6 In available at http://familydoctor.org/ lar and/or stromal cells outside of addition, endometriosis often occurs in online/famdocen/home/ the uterine cavity. There are gen- women with outflow obstruction, such as women/reproductive/ E erally three distinct clinical presentations: cervical stenosis, a transverse vaginal sep- gynecologic/476.html. endometrial implantation superficially on tum, and an imperforate hymen.7 the peritoneum; endometrial lined ovarian Although women with endometriosis have cysts (chocolate cysts) or ; higher volumes of refluxed menstrual blood and endometriotic nodules (a complex, solid and endometrial tissue,8 most women have mass of endometrial, adipose, and fibro- some component of retrograde menstrua- muscular tissue found between the rectum tion. The plasminogen activator inhibitor and ).1 However, further laparoscopic gene has been shown to increase the likeli- studies of the peritoneum also have shown hood of endometrial implantation after ret- nonclassic lesions, such as clear vesicles, red rograde menstruation.6 vesicles, or microscopic disease.2 Typically, The coelomic metaplasia theory of endo- ectopic endometrial tissue is found within metriosis proposes that the coelomic epi- the (Table 1).3 Although reported thelium of the peritoneal cavity retains in virtually all organ systems, extrapelvic deposition is exceedingly rare. Endometriosis is generally considered Table 1. Common Sites of a benign disease. However, several large Endometriosis cohort studies suggest that endometrio- sis is an independent risk factor for clear- Percentage cell carcinoma and endometrioid ovarian Site of patients 4 carcinoma. Ovaries 55 Anterior cul-de-sac 35 Etiology Posterior broad ligaments 35 The earliest and most widely accepted the- Posterior cul-de-sac 34 ory of endometriosis etiology is that refluxed Uterosacral ligaments 28 menstrual tissue enters the pelvic perito- neal cavity and embeds into other intra- Information from reference 3. abdominal areas.5,6 This theory is supported

DownloadedJanuary 15, from 2013 the ◆ American Volume Family87, Number Physician 2 website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2013 American Academy of FamilyAmerican Physicians. Family For the Physicianprivate, non -107 commercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Endometriosis SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence Clinical recommendation rating References

Transvaginal ultrasonography is the preferred imaging modality for C 26 women with suspected endometriosis. suppression therapies, such as oral contraceptives and A 26, 32, 36 gonadotropin-releasing hormone analogues, are effective for treating endometriosis pain. Surgical treatment of endometriosis improves pregnancy rates. A 26, 47 Ovulation suppression therapies do not improve pregnancy rates A 45 in patients with endometriosis.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evi- dence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

multipotential cells that can develop into the condition, with an average of 17.8 days endometriotic tissue. This explains rare spent in bed.17 cases of endometriosis in prepubertal girls, women with Müllerian agenesis, and men.6 Risk Factors Another theory is that endometrial tis- It has been reported that the risk of endome- sue can be transported to distant sites via triosis is six times higher in first-degree rela- lymphatic and vascular channels, which tives of women with severe endometriosis.9 explains rare cases of extra-abdominal However, a more recent case-control study endometriosis.6 Finally, newer research sug- showed that the familial impact on the inci- gests an immunologic component to the dence of endometriosis is not significant.18 development of endometriosis. Concentra- Early menarche and late menopause, tions of macrophages, leptin, tumor necro- which lead to increased exposure to men- sis factor-α, and interleukin-6 often are struation, are commonly cited risk factors higher in the abdominal fluid of women for endometriosis.5,19 However, epidemio- with endometriosis.6,9,10 logic studies are equivocal as to whether these are true risk factors or findings asso- Epidemiology ciated with the disease itself.20 Low body Endometriosis is an estrogen-dependent dis- mass index21,22 and higher caffeine or alco- ease predominantly affecting reproductive- hol consumption21 also are associated with aged women, with the highest incidence an increased risk of endometriosis. Table 2 among women 25 to 29 years of age.11 The includes possible risk factors for the prevalence of endometriosis in the general population is difficult to accurately assess because some women with the disease Table 2. Risk Factors for have limited or no symptoms. Some stud- Endometriosis ies suggest that it affects up to 10 percent of 12 reproductive-aged women. Endometriosis Early menarche is diagnosed in 21 to 40 percent of women First-degree relative with endometriosis 13 with infertility and in 70 to 90 percent of Late menopause 14 women with chronic pelvic pain. Low body mass index In the , endometriosis is Müllerian anomalies the third leading cause of gynecologic hos- Nulliparity 15 pitalizations. It is estimated that the dis- Prolonged menstruation (> five days) ease leads to $2,801 in health care costs Shorter lactation intervals and $1,023 in lost productivity at work Shorter menstrual cycles (< 28 days) 16 per patient annually. In one nationwide White race (compared with black race) survey, 50 percent of women with endo- metriosis reported spending entire days in Information from references 20 through 22. bed over the previous 12 months because of

108 American Family Physician www.aafp.org/afp Volume 87, Number 2 ◆ January 15, 2013 Endometriosis Table 3. Symptoms and Comorbidities Associated with Higher Rates of Endometriosis

Odds ratio Diagnosis (95% confidence The diagnosis of endometriosis in primary Symptoms/comorbidities interval) care is initially clinical and based on history Infertility/subfertility 8.2 (6.9 to 9.9) and physical examination findings. Histologic Dysmenorrhea 8.1 (7.2 to 9.3) confirmation is usually achieved with the Ovarian cysts 7.3 (5.7 to 9.4) detection of extrauterine endometrial cells on Dyspareunia and/or 6.8 (5.7 to 8.2) laparoscopy. Less invasive diagnostic tests are being pursued. Transvaginal ultrasonogra- Abdominal or pelvic pain 5.2 (4.7 to 5.7) phy can reliably detect cystic endometriomas Pelvic inflammatory 3.0 (2.5 to 3.6) (89 percent sensitivity, 91 percent specific- disease ity) and is considered the imaging modality Irritable bowel syndrome 1.6 (1.3 to 1.8) of choice,26,27 although the test does not reli- ably detect smaller endometrial implants. The Information from reference 23. cancer antigen 125 assay has been extensively researched, but a large systematic review of 23 studies shows limited overall value in disease.20-22 Oral contraceptives and regu- the diagnosis of endometriosis. The cancer lar exercise (i.e., more than four hours per antigen 125 level is often elevated in women week) may decrease the risk.5,21 with endometriosis, but its specificity for the disease is low.28 Magnetic resonance imag- Clinical Presentation ing also is being explored, particularly for The clinical presentation of endometriosis is deeper rectosigmoid and ureteral infiltrating highly variable and ranges from debilitating lesions, but it is not a standard diagnostic tool pelvic pain and infertility to no symptoms. because of its low sensitivity.29 Table 3 lists the symptoms and comorbidi- ties that are associated with higher rates of Treatment endometriosis.23 In a large case-control study Nonsteroidal anti-inflammatory drugs in the , 73 percent of women (NSAIDs) are often the first-line treatment with endometriosis reported dysmenorrhea, for endometriosis, followed by hormone abdominal or pelvic pain, or menorrhagia, compared with 20 percent of women without the disease.23 Many women with endome- Table 4. Differential Diagnosis of Symptoms Commonly triosis present with nonspecific symptoms, Associated with Endometriosis such as chronic lower back pain or abdomi- nal pain, which may delay diagnosis. Table 4 Symptom Selected alternative diagnoses includes the differential diagnosis of common Adnexal masses Benign and malignant ovarian cysts, symptoms of endometriosis.5 It takes an aver- hydrosalpinges age of 11.7 years for endometriosis to be diag- Chronic lower Irritable bowel syndrome, neuropathic pain, nosed in a woman with symptoms.24 abdominal pain adhesions, pelvic vascular congestion Similarly, objective physical examina- Chronic lower back pain Musculoskeletal strain tion findings are limited and nonspecific. Dyschezia (i.e., difficulty Constipation, anal fissures Although many women with endometrio- with defecation) sis will have normal examination findings, Dysmenorrhea , physiologic etiology some will exhibit tenderness of the posterior Dyspareunia Psychosexual problems, vaginal atrophy, fornix, limited motion of the or ova- infectious or , vulvodynia ries, or an . Some women will Dysuria Urinary tract infection, interstitial cystitis have diffuse tenderness on pelvic exami- Infertility , luteal phase deficiency, cervical or tubal structural or infectious pathology, nation. However, in women undergoing male factor infertility evaluation for infertility, uterosacral nodu- larity with associated tenderness is pathog- Adapted with permission from Farquhar C. Endometriosis. BMJ. 2007;334(7587):249. nomonic for endometriosis.25

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Treatment Evidence

NSAIDs A 2009 Cochrane review including only one small RCT of naproxen versus placebo showed no conclusive evidence that NSAIDs improve pain; however, because NSAIDs are effective for primary dysmenorrhea, consensus opinion suggests they are reasonable as a first-line treatment for suspected endometriosis30 Combination oral A 2007 Cochrane review including only one study comparing contraceptives combination oral contraceptives with gonadotropin-releasing hormone analogues showed that both were comparable for pain relief 31; a Japanese RCT showed that low-dose combined oral contraceptives improved pain compared with placebo32 Small RCTs show that oral medroxyprogesterone (Provera) and depot medroxyprogesterone (Depo-Provera, Depo-subQ Provera) are beneficial for pain33,34 -releasing Small nonrandomized studies show possible benefit for pain33,35 intrauterine system (Mirena) Gonadotropin-releasing A 2010 Cochrane review showed effectiveness36; however, adverse hormone analogues effects (i.e., menopausal symptoms) limit its use Danazol A 2007 Cochrane review showed effectiveness37; however, androgenic adverse effects limit its use

NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized controlled trial. Information from references 30 through 37.

therapy. Laparoscopy can be used to confirm A double-blind, randomized controlled trial the diagnosis before additional treatments are of 100 women with endometriosis demon- pursued; empiric therapy with another sup- strated that low-dose combination oral con- pressive is also an option. Table 5 traceptives improved endometriosis pain summarizes evidence-based therapies.30-37 compared with placebo.32 Another study Figure 1 is an algorithm for treating endome- showed that combination oral contraceptives triosis in primary care. were less effective at six months compared with gonadotropin-releasing hormone (GnRH) NONSTEROIDAL ANTI-INFLAMMATORY DRUGS analogues, although both significantly A Cochrane review evaluated NSAIDs in the improved symptoms after 12 months.38 Com- treatment of endometriosis, but included bination oral contraceptives have significantly only one randomized controlled trial (n = 24), fewer adverse effects than GnRH analogues. which compared naproxen with placebo.30 A small, prospective, nonblinded, cohort There was no difference in pain relief study compared the ethinyl / between naproxen and placebo, and there (Nuvaring) with was no evidence that one NSAID is superior. the /ethinyl estradiol trans- NSAIDs often are attempted first because dermal patch (Ortho Evra) in patients with they are beneficial in women with primary endometriosis.39 Although continuous use of dysmenorrhea, are available over the counter, both treatments reduced pain, the ring was and are relatively safe. Although endometri- superior for dysmenorrhea. Patient satisfac- osis is a condition of secondary dysmenor- tion also seemed higher in patients using the rhea, it seems reasonable to consider NSAIDs ring. Continuous use of these treatments as a first-line treatment in women with sus- resulted in more breakthrough bleeding pected endometriosis. compared with cyclic use.

COMBINATION ESTROGEN/PROGESTIN -ONLY CONTRACEPTIVES CONTRACEPTIVES Medroxyprogesterone (oral [Provera] or Combination oral contraceptives are more depot injection [Depo-Provera]) may effective than placebo at reducing dysmen- improve symptoms of endometriosis com- orrhea in women with endometriosis.31-33 pared with placebo.33 Two trials comparing

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a lower-dose depot medroxyprogesterone pain and treat infertility. Excision of endo- (Depo-subQ Provera) with the GnRH ana- metriomas will more effectively improve logue leuprolide (Lupron) showed compa- pregnancy rates than a drainage and abla- rable improvement in pain.34,40 Both trials tion technique, but there is little evidence indicated that depot medroxyprogesterone on the success of surgical treatment in resulted in less bone loss and hypoestrogenic advanced disease.26,45 If a woman with endo- adverse effects than leuprolide; however, metriosis does not desire future pregnancy depot medroxyprogesterone labels include and all medical treatments and conservative U.S. Food and Drug Administration boxed surgical therapies have been ineffective, a warnings for bone loss. Two studies compar- hysterectomy may be performed. ing (a new selective progestin that is not yet available in the United States) with FUTURE TREATMENTS GnRH analogues also showed comparable Several are under evalua- improvement in pain.41,42 tion for the treatment of endometriosis, A small study showed that the etonoges- including (Mifeprex); aro- trel subdermal implant (Implanon) was as matase inhibitors (i.e., letrozole [Femara], effective as depot medroxyprogesterone for anastrozole [Arimidex], and endometriosis pain.43 Small nonrandomized studies have shown a possible improvement in endometriosis pain with the levonorgestrel- Treatment of Endometriosis releasing intrauterine system (Mirena).33,35 Woman presents with pelvic pain GONADOTROPIN-RELEASING HORMONE and presumed endometriosis ANALOGUES If NSAIDs and hormonal contraceptives are Treat empirically with a high-dose ineffective, the next step is treatment with a nonsteroidal anti-inflammatory drug GnRH analogue such as leuprolide or gos- erelin (Zoladex). GnRH analogue therapy No improvement in pain downregulates the pituitary, resulting in “medical menopause,” 44 and has been shown to improve pain in women with endometrio- sis.36 However, the therapy causes adverse Pregnancy desired Pregnancy not desired effects, such as hot flashes, night sweats, and possible bone loss, in many women. To miti- A Refer to gynecologist Treat with extended-cycle contraception: gate the menopausal symptoms, reinitiating for further evaluation Combination estrogen/progestin with low-dose estrogen and treatment (e.g., contraceptive (monophasic combined oral gonadotropin-releasing contraceptive, vaginal ring [Nuvaring], and progestin is common. hormone analogue, transdermal patch [Ortho Evra]) danazol, laparoscopy) Long-acting progestin-only contraceptive DANAZOL (oral medroxyprogesterone [Provera], Danazol, an , is effective in the depot medroxyprogesterone [Depo- Provera, Depo-subQ Provera], treatment of pelvic pain associated with etonogestrel subdermal implant endometriosis.37 However, androgenic [Implanon], levonorgestrel-releasing adverse effects, such as , hirsutism, and intrauterine system [Mirena]) male pattern baldness, often limit its use.

The drug has several U.S. Food and Drug Pain not controlled Administration boxed warnings, including the risk of thrombosis and teratogenicity. Go to A SURGICAL OPTIONS

Laparoscopic ablation of deposits and exci- Figure 1. Algorithm for the treatment of endometriosis in primary sion of endometriomas are options to relieve care.

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[Aromasin]); Chinese herbal medications; JENNIFER EDGOOSE, MD, MPH, is an assistant professor (a 19-nortestosterone derivative in the Department of Family Medicine at the University of Wisconsin School of Medicine and Public Health. that has antiprogestational and antiestro- genic properties; not available in the United Address correspondence to Sarina Schrager, MD, MS, University of Wisconsin, 1100 Delaplaine Ct., Madison, States); immunomodulators (i.e., pent- WI 53715 (e-mail: [email protected]). Reprints are not oxifylline [Trental] and interferon); and available from the authors. 33 selective estrogen receptor modulators. Author disclosure: No relevant financial affiliations to Acupuncture may also be effective in the disclose. treatment of pain.46 REFERENCES Managing Endometriosis-Related Infertility 1. Bulun SE. Endometriosis. N Engl J Med. 2009; 360(3):268-279. Women with infertility due to endome- 2. Eltabbakh GH, Bower NA. Laparoscopic in triosis usually will undergo laparoscopy. In endometriosis. Minerva Ginecol. 2008;60(4):323-330. women with mild endometriosis diagnosed 3. Jenkins S, Olive DL, Haney AF. Endometriosis: pathoge- by laparoscopy, surgical treatment of lesions netic implications of the anatomic distribution. Obstet Gynecol. 1986;67(3):335-338. improves pregnancy rates compared with no 4. Van Gorp T, Amant F, Neven P, Vergote I, Moerman 26,47 treatment of lesions. P. Endometriosis and the development of malignant A Cochrane review evaluated 25 ran- tumours of the pelvis. A review of literature. Best Pract domized controlled trials comparing oral Res Clin Obstet Gynaecol. 2004;18(2):349-371. 5. Farquhar C. Endometriosis. BMJ. 2007;334(7587): contraceptives, progestins, and danazol 249-253. with placebo to determine 6. Bedaiwy MA, Abdel-Aleem MA, Miketa A, Falcone T. the effectiveness of tempo- Endometriosis: a critical appraisal of the advances and The diagnosis of endome- rary ovulation suppression for the controversies of a challenging health problem. triosis in primary care is Minerva Ginecol. 2009;61(4):285-298. endometriosis-related infer- 7. Olive DL, Henderson DY. Endometriosis and mullerian initially clinical and based 45 tility. The review measured anomalies. Obstet Gynecol. 1987;69(3 pt 1):412-415. on history and physical outcomes related to effects on 8. Halme J, Hammond MG, Hulka JF, Raj SG, Talbert examination findings. subsequent fertility, such as LM. Retrograde menstruation in healthy women and in patients with endometriosis. Obstet Gynecol. live birth after 20 weeks’ ges- 1984;64(2):151-154. tation and clinical pregnancy (evidenced 9. Giudice LC, Kao LC. Endometriosis. Lancet. 2004; by fetal heart motion and gestational sac) 364(9447):1789-1799. compared with adverse events (i.e., mis- 10. Harada T, Taniguchi F, Izawa M, et al. Apoptosis and carriage, ectopic pregnancy, fetal abnor- endometriosis. Front Biosci. 2007;12:3140-3151. 11. Missmer SA, Hankinson SE, Spiegelman D, Barbieri malities, adverse drug effects). The review RL, Marshall LM, Hunter DJ. Incidence of laparo- showed that ovulation suppression had no scopically confirmed endometriosis by demographic, effect on subsequent fertility compared anthropometric, and lifestyle factors. Am J Epidemiol. 2004;160(8):784-796. with placebo. 12. Wheeler JM. Epidemiology of endometriosis-associated Data Sources: We searched PubMed, the Cochrane infertility. J Reprod Med. 1989;34(1):41-46. Database of Systematic Reviews, the National Guideline 13. Strathy JH, Molgaard CA, Coulam CB, Melton LJ III. Clearinghouse, and Clinical Evidence using the search Endometriosis and infertility: a laparoscopic study of terms endometriosis, etiology of endometriosis, epidemi- endometriosis among fertile and infertile women. Fertil ology of endometriosis, treatment of endometriosis, and Steril. 1982;38(6):667-672. infertility associated with endometriosis. Search dates: 14. Ozawa Y, Murakami T, Terada Y, et al. Management December 2010 to January 2011. of the pain associated with endometriosis: an update of the painful problems. Tohoku J Exp Med. 2006; 210 (3):175-188. The Authors 15. Velebil P, Wingo PA, Xia Z, Wilcox LS, Peterson HB. Rate SARINA SCHRAGER, MD, MS, is a professor in the Depart- of hospitalization for gynecologic disorders among reproductive-age women in the United States. Obstet ment of Family Medicine at the University of Wisconsin Gynecol. 1995;86(5):764-769. School of Medicine and Public Health in Madison. 16. Simoens S, Hummelshoj L, D’Hooghe T. Endometriosis: JULIANNE FALLERONI, DO, MPH, is an assistant professor cost estimates and methodological perspective. Hum in the Department of Family Medicine at the University of Reprod Update. 2007;13(4):395-404. Wisconsin School of Medicine and Public Health. 17. Kjerulff KH, Erickson BA, Langenberg PW. Chronic

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gynecological conditions reported by US women: 34. Schlaff WD, Carson SA, Luciano A, Ross D, Bergqvist findings from the National Health Interview Survey, A. Subcutaneous injection of depot medroxyproges- 1984 to 1992. Am J Public Health. 1996;86(2):195-199. terone acetate compared with leuprolide acetate in the 18. Nouri K, Ott J, Krupitz B, Huber JC, Wenzl R. Family treatment of endometriosis-associated pain. Fertil Steril. incidence of endometriosis in first-, second-, and third- 2006;85(2):314-325. degree relatives: case-control study. Reprod Biol Endo- 35. Lockhat FB, Emembolu JO, Konje JC. The efficacy, crinol. 2010;8:85. side-effects and continuation rates in women with 19. Missmer SA, Hankinson SE, Spiegelman D, et al. Repro- symptomatic endometriosis undergoing treatment ductive history and endometriosis among premeno- with an intra-uterine administered pausal women. Obstet Gynecol. 2004;104(5 pt 1): (levonorgestrel): a 3 year follow-up. Hum Reprod. 965-974. 2005;20(3):789-793. 20. Treloar SA, Bell TA, Nagle CM, Purdie DM, Green AC. 36. Brown J, Pan A, Hart RJ. Gonadotrophin-releasing hor- Early menstrual characteristics associated with subse- mone analogues for pain associated with endometrio- quent diagnosis of endometriosis. Am J Obstet Gynecol. sis. Cochrane Database Syst Rev. 2010;(12):CD008475. 2010;202(6):534.e1-6. 37. Selak V, Farquhar C, Prentice A, Singla A. Danazol for 21. Ozkan S, Murk W, Arici A. Endometriosis and infertility: pelvic pain associated with endometriosis. Cochrane epidemiology and evidence-based treatments. Ann N Y Database Syst Rev. 2007;(4):CD000068. Acad Sci. 2008;1127:92-100. 38. Ferrero S, Remorgida V, Venturini PL. Endometriosis. 22. Hediger ML, Hartnett HJ, Louis GM. Association of Clin Evid (Online). August 13, 2010. http://clinical- endometriosis with body size and figure. Fertil Steril. evidence.bmj.com/ceweb/conditions/woh/0802/0802- 2005;84(5):1366-1374. get.pdf [login required]. Accessed February 15, 2011. 23. Ballard KD, Seaman HE, de Vries CS, Wright JT. Can 39. Vercellini P, Barbara G, Somigliana E, Bianchi S, Abbiati symptomatology help in the diagnosis of endometrio- A, Fedele L. Comparison of contraceptive ring and sis? Findings from a national case-control study—part 1. patch for the treatment of symptomatic endometriosis. BJOG. 2008;115 (11):1382-1391. Fertil Steril. 2010;93(7):2150-2161. 24. Hadfield R, Mardon H, Barlow D, Kennedy S. Delay in the 40. Crosignani PG, Luciano A, Ray A, Bergqvist A. Subcu- diagnosis of endometriosis: a survey of women from the taneous depot medroxyprogesterone acetate versus USA and the UK. Hum Reprod. 1996;11(4):878-880. leuprolide acetate in the treatment of endometriosis- associated pain. Hum Reprod. 2006;21(1):248-256. 25. Matorras R, Rodríguez F, Pijoan JI, et al. Are there any clinical signs and symptoms that are related to endo- 41. Strowitzki T, Marr J, Gerlinger C, Faustmann T, Seitz C. metriosis in infertile women? Am J Obstet Gynecol. Dienogest is as effective as leuprolide acetate in treat- 1996;174(2):620-623. ing the painful symptoms of endometriosis: a 24-week, randomized, multicentre, open-label trial. Hum Reprod. 26. Practice bulletin no. 114: management of endometrio- 2010;25(3):633-641. sis. Obstet Gynecol. 2010;116(1):223-236. 42. Harada T, Momoeda M, Taketani Y, et al. Dienogest is 27. Alcázar JL, Laparte C, Jurado M, López-García G. The as effective as intranasal buserelin acetate for the relief role of transvaginal ultrasonography combined with of pain symptoms associated with endometriosis—a color velocity imaging and pulsed Doppler in the diagno- randomized, double-blind, multicenter, controlled trial. sis of . Fertil Steril. 1997;67(3):487-491. Fertil Steril. 2009;91(3):675-681. 28. Mol BW, Bayram N, Lijmer JG, et al. The performance of 43. Walch K, Unfried G, Huber J, et al. Implanon versus CA-125 measurement in the detection of endometrio- medroxyprogesterone acetate: effects on pain scores sis: a meta-analysis. Fertil Steril. 1998;70 ( 6):1101-1108. in patients with symptomatic endometriosis—a pilot 29. Brosens I, Puttemans P, Campo R, Gordts S, Kinkel study. Contraception. 2009;79(1):29-34. K. Diagnosis of endometriosis: pelvic endoscopy and 44. de Ziegler D, Borghese B, Chapron C. Endometriosis and imaging techniques. Best Pract Res Clin Obstet Gynae- infertility: pathophysiology and management. Lancet. col. 2004;18(2):285-303. 2010;376(9742):730-738. 30. Allen C, Hopewell S, Prentice A, Gregory D. Nonste- 45. Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow roidal anti-inflammatory drugs for pain in women DM, Vandekerckhove P. Ovulation suppression with endometriosis. Cochrane Database Syst Rev. for endometriosis. Cochrane Database Syst Rev. 2009;(2):CD004753. 2007;(3):CD000155. 31. Davis L, Kennedy SS, Moore J, Prentice A. Modern 46. Rubi-Klein K, Kucera-Sliutz E, Nissel H, et al. Is acupunc- combined oral contraceptives for pain associated with ture in addition to conventional medicine effective as endometriosis. Cochrane Database Syst Rev. 2007;(3): pain treatment for endometriosis? A randomised con- CD001019. trolled cross-over trial. Eur J Obstet Gynecol Reprod 32. Harada T, Momoeda M, Taketani Y, Hoshiai H, Ter- Biol. 2010;153(1):90-93. akawa N. Low-dose for 47. Jacobson TZ, Duffy JM, Barlow D, Farquhar C, Koninckx dysmenorrhea associated with endometriosis: a pla- PR, Olive D. Laparoscopic surgery for subfertility associ- cebo-controlled, double-blind, randomized trial. Fertil ated with endometriosis. Cochrane Database Syst Rev. Steril. 2008;90 (5):1583-1588. 2010;(1):CD001398. 33. Ferrero S, Remorgida V, Venturini PL. Current pharma- cotherapy for endometriosis. Expert Opin Pharmaco- ther. 2010 ;11(7):1123-1134.

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